Summary of project PR001933
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001933. The data can be accessed directly via it's Project DOI: 10.21228/M8VM8W This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR001933 |
| Project DOI: | doi: 10.21228/M8VM8W |
| Project Title: | Inhibition of Asparagine Synthetase Effectively Retards Polycystic Kidney Disease Progression. |
| Project Summary: | Polycystic Kidney Disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against ASNS in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4-ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD control kidneys treated with ASNS-ASOScr-ASO revealed major changes in the mutants, several of which are rescued by ASNS silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by ASNS-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with ASNS-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD. Altogether, targeted metabolomics analysis performed in Tam-Cre;Pkd1ΔC/flox mouse model kidneys corroborates the central role of ASNS in the metabolic rewiring occurring in PKD, highlighting the therapeutic potential of its inhibition. |
| Institute: | San Raffaele University |
| Last Name: | Stefanoni |
| First Name: | Davide |
| Address: | Via Olgettina 58, Milan, Milan, 20132, Italy |
| Email: | stefanoni.davide@hsr.it |
| Phone: | +393337686005 |
Summary of all studies in project PR001933
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003111 | Inhibition of Asparagine Synthetase Effectively Retards Polycystic Kidney Disease Progression, investigated with targeted metabolomics in Tam-Cre;Pkd1ΔC/flox mouse model kidneys. | Mus musculus | San Raffaele University | MS | 2024-04-30 | 1 | 18 | Uploaded data (2.1G)* |
| ST003113 | Inhibition of Asparagine Synthetase Effectively Retards Polycystic Kidney Disease Progression, investigated with targeted tracing metabolomics analysis in MEF cells using 15N2-glutamine. | Mus musculus | San Raffaele University | MS | 2024-04-30 | 1 | 46 | Uploaded data (4.7G)* |
